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Carsten A Wagner - One of the best experts on this subject based on the ideXlab platform.
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Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis
Journal of Nephrology, 2018Co-Authors: Nilufar Mohebbi, Carsten A WagnerAbstract:Distal renal tubular acidosis (dRTA) is a tubular disorder with a primary defect of urinary acidification and acid excretion in the collecting duct system. Consequently, patients develop hyperchloremic metabolic acidosis with an inappropriately alkaline urine. Inherited forms of dRTA are due to mutations in at least three distinct genes: SLC4A1, ATP6V1B1, ATP6V0A4 . Mutations in SLC4A1 -(AE1) are inherited either in an autosomal dominant manner or in a recessive one. ATP6V1B and ATP6V0A4 mutations affect two different subunits of the vacuolar H^+-ATPase proton-pump, the B1 and a4 subunits, and are inherited in an autosomal recessive manner. Clinical manifestations of inherited forms of dRTA usually occur during infancy or childhood. However, heterozygous carriers of ATP6V1B1 and ATP6V0A4 mutations may have a higher risk of developing nephrolithiasis and nephrocalcinosis in adulthood, respectively. In full forms of dRTA, patients may present with mild clinical symptoms, such as mild metabolic acidosis and incidental detection of kidney stones, as well as with more severe manifestations such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. Progressive sensorineural hearing loss develops in the majority of patients with recessive dRTA ( ATP6V1B1 and ATP6V0A4 mutations). Some patients with recessive dRTA may also develop abnormal widening of the vestibular aqueduct. This review will discuss our current understanding of the pathophysiology of inherited forms of dRTA, diagnosis and prognosis of patients, and therapy.
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The ammonia transporter RhCG modulates urinary acidification by interacting with the vacuolar proton-ATPases in renal intercalated cells
Kidney International, 2017Co-Authors: Soline Bourgeois, Lisa Bounoure, Isabelle Mouro-chanteloup, Yves Colin, Dennis Brown, Carsten A WagnerAbstract:Ammonium, stemming from renal ammoniagenesis, is a major urinary proton buffer and is excreted along the collecting duct. This process depends on the concomitant secretion of ammonia by the ammonia channel RhCG and of protons by the vacuolar-type proton-ATPase pump. Thus, urinary ammonium content and urinary acidification are tightly linked. However, mice lacking Rhcg excrete more alkaline urine despite lower urinary ammonium, suggesting an unexpected role of Rhcg in urinary acidification. RhCG and the B1 and B2 proton-ATPase subunits could be co-immunoprecipitated from kidney. In ex vivo microperfused cortical collecting ducts (CCD) proton-ATPase activity was drastically reduced in the absence of Rhcg. Conversely, overexpression of RhCG in HEK293 cells resulted in higher proton secretion rates and increased B1 proton-ATPase mRNA expression. However, in kidneys from Rhcg -/- mice the expression of only B1 and B2 subunits was altered. Immunolocalization of proton-ATPase subunits together with immuno-gold detection of the A proton-ATPase subunit showed similar localization and density of staining in kidneys from Rhcg +/+ and Rhcg -/- mice. In order to test for a reciprocal effect of intercalated cell proton-ATPases on Rhcg activity, we assessed Rhcg and proton-ATPase activities in microperfused CCD from ATP6V1B1 -/- mice and showed reduced proton-ATPase activity without altering Rhcg activity. Thus, RhCG and proton-ATPase are located within the same cellular protein complex. RhCG may modulate proton-ATPase function and urinary acidification, whereas proton-ATPase activity does not affect RhCG function. This mechanism may help to coordinate ammonia and proton secretion beyond physicochemical driving forces.
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renal β intercalated cells maintain body fluid and electrolyte balance
Journal of Clinical Investigation, 2013Co-Authors: Victor Gueutin, Carsten A Wagner, Dominique Eladari, Marion Vallet, Maximilien Jayat, Janos Petipeterdi, Nicolas Corniere, Francoise Leviel, Fabien Sohet, Régine ChambreyAbstract:Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (ATP6V1B1-/- mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na(+)-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E2 (PGE2) and ATP levels in ATP6V1B1-/- mice. Inhibition of PGE2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in β-ICs induced release of PGE2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE2 paracrine signaling originating from β-ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with dRTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure.
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homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss
Clinical Genetics, 2013Co-Authors: Nilufar Mohebbi, R Vargaspoussou, S C A Hegemann, B Schuknecht, Andreas D Kistler, Rudolf P Wuthrich, Carsten A WagnerAbstract:Mohebbi N, Vargas-Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wuthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near-normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non-consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.
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Postnatal expression of transport proteins involved in acid–base transport in mouse kidney
Pflügers Archiv, 2004Co-Authors: Brenda Bonnici, Carsten A WagnerAbstract:The kidney plays a major role in maintaining and controlling systemic acid–base homeostasis by reabsorbing bicarbonate and secreting protons and acid-equivalents, respectively. During postnatal kidney development and adaptation to changing diets, plasma bicarbonate levels are increasing, the capacity for urinary acidification maturates, and the final morphology and distribution of intercalated cells is achieved. In adult kidney, at least two types of intercalated cells (IC) are found along the collecting duct characterised either by the expression of AE1 (type A IC) or pendrin (non-type A IC) where non-type A IC are found only in the convoluted distal tubule, connecting tubule and cortical collecting duct. Here we investigated in mouse kidney the relative mRNA abundance, protein expression levels and distribution of several proteins involved in renal acid–base transport, namely, the Na^+/HCO_3 ^− cotransporter NBC1 (SLC4A4), the Na^+/H^+-exchanger NHE3 (SLC9A3), two subunits of the vacuolar H^+-ATPase [ATP6V0A4 (a4), ATP6V1B1 (B1)], the Cl^−/HCO_3 ^− exchangers AE1 (SLC4A1) and pendrin (SLC26A4). Relative mRNA abundance of all transport proteins was lowest at day 3 after birth and increased thereafter in parallel with protein levels. The numbers of type A and non-type A IC in the cortical collecting duct (CCD) increased from day 3 to days 18 and 24, whereas the number of IC in the CCD with apical staining for the vacuolar H^+-ATPase subunits a4 and B1 decreased from day 3 to days 18 and 24, respectively. In addition, cells with characteristics of non-type A IC (pendrin expression, basolateral expression of vacuolar H^+-ATPase subunits) were found in the inner and outer medulla 3 days after birth but were absent from the medulla of 24-day-old mice. Taken together, these results demonstrate massive changes in mRNA and protein expression levels of several acid–base transporters during postnatal kidney maturation and also show changes in intercalated cell phenotype in the medulla during these processes.
Dennis Brown - One of the best experts on this subject based on the ideXlab platform.
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The ammonia transporter RhCG modulates urinary acidification by interacting with the vacuolar proton-ATPases in renal intercalated cells
Kidney International, 2017Co-Authors: Soline Bourgeois, Lisa Bounoure, Isabelle Mouro-chanteloup, Yves Colin, Dennis Brown, Carsten A WagnerAbstract:Ammonium, stemming from renal ammoniagenesis, is a major urinary proton buffer and is excreted along the collecting duct. This process depends on the concomitant secretion of ammonia by the ammonia channel RhCG and of protons by the vacuolar-type proton-ATPase pump. Thus, urinary ammonium content and urinary acidification are tightly linked. However, mice lacking Rhcg excrete more alkaline urine despite lower urinary ammonium, suggesting an unexpected role of Rhcg in urinary acidification. RhCG and the B1 and B2 proton-ATPase subunits could be co-immunoprecipitated from kidney. In ex vivo microperfused cortical collecting ducts (CCD) proton-ATPase activity was drastically reduced in the absence of Rhcg. Conversely, overexpression of RhCG in HEK293 cells resulted in higher proton secretion rates and increased B1 proton-ATPase mRNA expression. However, in kidneys from Rhcg -/- mice the expression of only B1 and B2 subunits was altered. Immunolocalization of proton-ATPase subunits together with immuno-gold detection of the A proton-ATPase subunit showed similar localization and density of staining in kidneys from Rhcg +/+ and Rhcg -/- mice. In order to test for a reciprocal effect of intercalated cell proton-ATPases on Rhcg activity, we assessed Rhcg and proton-ATPase activities in microperfused CCD from ATP6V1B1 -/- mice and showed reduced proton-ATPase activity without altering Rhcg activity. Thus, RhCG and proton-ATPase are located within the same cellular protein complex. RhCG may modulate proton-ATPase function and urinary acidification, whereas proton-ATPase activity does not affect RhCG function. This mechanism may help to coordinate ammonia and proton secretion beyond physicochemical driving forces.
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the v atpase b1 subunit promoter drives expression of cre recombinase in intercalated cells of the kidney
Kidney International, 2009Co-Authors: Lance R Miller, Dennis Brown, Olivia Lucero, Kent A Riemondy, Brett K Baumgartner, Sylvie Breton, Raoul D. NelsonAbstract:The collecting duct of the kidney is composed of two morphologically and physiologically distinct cell types, principal and intercalated cells. To better understand intercalated cell function we generated a transgenic mouse expressing Cre recombinase under the control of a cell type- specific promoter. We used 7 kb of the ATP6V1B1 5′ untranslated region (B1 promoter), a gene found in the intercalated cells of the kidney and the male reproductive tract. We first crossed these B1-Cre transgenic mice with the ROSA26-loxP-stop-loxP-yellow fluorescent protein reporter mice to assess the specificity of Cre expression. Immunohistochemistry and confocal fluorescence microscopy showed that Cre is selectively active in all intercalated cells (type A, type B, and non-A/B cells) within the collecting duct and most cells of the connecting segment. About half of the principal cells of the connecting segment also expressed Cre, a pattern also seen in B1-driven enhanced green fluorescent protein transgenic mice. Cre was found to be active in the male reproductive tract and at a low level in limited non-ATP6V1B1 expressing tissues. The B1-Cre transgenic mice are healthy, breed normally, produce regular sized litters, and transmit the transgene in Mendelian fashion. This new cell-specific Cre expressing mouse should prove useful for the study of intercalated cell physiology and development.
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segmental expression of the bradykinin type 2 receptor in rat efferent ducts and epididymis and its role in the regulation of aquaporin 9
Biology of Reproduction, 2009Co-Authors: Clemence Belleannee, Dennis Brown, N Da Silva, Winnie W C Shum, Mireille Marsolais, Raynald Laprade, Sylvie BretonAbstract:Water and solute transport in the efferent ducts and epididymis are important for the establishment of the appropriate luminal environment for sperm maturation and storage. Aquaporin 9 (AQP9) is the main water channel in the epididymis, but its regulation is still poorly understood. Components of the kinin-kallikrein system (KKS), leading to the production of bradykinin (BK), are highly expressed in the lumen of the male reproductive tract. We report here that the epididymal luminal fluid contains a significant amount of BK (2 nM). RT-PCR performed on epididymal epithelial cells isolated by laser capture microdissection (LCM) showed abundant BK type 2 receptor (Bdkrb2) mRNA expression but no type 1 receptor (Bdkrb1). Double-immunofluorescence staining for BDKRB2 and the anion exchanger AE2 (a marker of efferent duct ciliated cells) or the V-ATPase E subunit, official symbol ATP6V1E1 (a marker of epididymal clear cells), showed that BDKRB2 is expressed in the apical pole of nonciliated cells (efferent ducts) and principal cells (epididymis). Triple labeling for BDKRB2, AQP9, and ATP6V1E1 showed that BDKRB2 and AQP9 colocalize in the apical stereocilia of principal cells in the cauda epididymidis. While uniform Bdkrb2 mRNA expression was detected in the efferent ducts and along the epididymal tubule, marked variations were detected at the protein level. BDKRB2 was highest in the efferent ducts and cauda epididymidis, intermediate in the distal initial segment, moderate in the corpus, and undetectable in the proximal initial segment and the caput. Functional assays on tubules isolated from the distal initial segments showed that BK significantly increased AQP9-dependent glycerol apical membrane permeability. This effect was inhibited by BAPTA-AM, demonstrating the participation of calcium in this process. This study, therefore, identifies BK as an important regulator of AQP9.
Raoul D. Nelson - One of the best experts on this subject based on the ideXlab platform.
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Reducing αENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading
American Journal of Physiology-renal Physiology, 2015Co-Authors: Soren Brandt Poulsen, Jeppe Praetorius, Helle Hasager Damkier, Lance Edward Miller, Raoul D. Nelson, Edith Hummler, Birgitte Monster ChristensenAbstract:Genetic inactivation of the epithelial Na(+) channel α-subunit (αENaC) in the renal collecting duct (CD) does not interfere with Na(+) and K(+) homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of αENaC in the CNT. Knockout mice with αENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1a(lox/lox) mice and ATP6V1B1::Cre mice. With a standard diet, plasma Na(+) concentration ([Na(+)]) and [K(+)], and urine Na(+) and K(+) output were unaffected. Seven days of Na(+) restriction (0.01% Na(+)) led to a higher urine Na(+) output only on days 3-5, and after 7 days plasma [Na(+)] and [K(+)] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K(+) diet and showed lower food intake and relative body weight, lower plasma [Na(+)], higher fractional excretion (FE) of Na(+), higher plasma [K(+)], and lower FE of K(+). The higher FE of Na(+) coincided with lower abundance and phosphorylation of the Na(+)-Cl(-) cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K(+) loading.
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SLC26A4 targeted to the endolymphatic sac rescues hearing and balance in Slc26a4 mutant mice.
PLoS genetics, 2013Co-Authors: Joel D. Sanneman, Raoul D. Nelson, Donald G. Harbidge, Fei Zhou, Taku Ito, Nicolas Picard, Dominique Eladari, Régine Chambrey, Tracy MiesnerAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.
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the v atpase b1 subunit promoter drives expression of cre recombinase in intercalated cells of the kidney
Kidney International, 2009Co-Authors: Lance R Miller, Dennis Brown, Olivia Lucero, Kent A Riemondy, Brett K Baumgartner, Sylvie Breton, Raoul D. NelsonAbstract:The collecting duct of the kidney is composed of two morphologically and physiologically distinct cell types, principal and intercalated cells. To better understand intercalated cell function we generated a transgenic mouse expressing Cre recombinase under the control of a cell type- specific promoter. We used 7 kb of the ATP6V1B1 5′ untranslated region (B1 promoter), a gene found in the intercalated cells of the kidney and the male reproductive tract. We first crossed these B1-Cre transgenic mice with the ROSA26-loxP-stop-loxP-yellow fluorescent protein reporter mice to assess the specificity of Cre expression. Immunohistochemistry and confocal fluorescence microscopy showed that Cre is selectively active in all intercalated cells (type A, type B, and non-A/B cells) within the collecting duct and most cells of the connecting segment. About half of the principal cells of the connecting segment also expressed Cre, a pattern also seen in B1-driven enhanced green fluorescent protein transgenic mice. Cre was found to be active in the male reproductive tract and at a low level in limited non-ATP6V1B1 expressing tissues. The B1-Cre transgenic mice are healthy, breed normally, produce regular sized litters, and transmit the transgene in Mendelian fashion. This new cell-specific Cre expressing mouse should prove useful for the study of intercalated cell physiology and development.
Constantinos Deltas - One of the best experts on this subject based on the ideXlab platform.
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founder mutations in the ATP6V1B1 geneexplain most cypriot cases of distal renal tubular acidosis first prenatal diagnosis
Nephron Clinical Practice, 2011Co-Authors: Avraam Elia, Konstantinos Voskarides, Panayiota Demosthenous, Aikaterini Michalopoulou, Mariaadamantia Malliarou, Eleni Georgaki, Yiannis Athanasiou, Charalambos Patsias, Alkis Pierides, Constantinos DeltasAbstract:Aims: To investigate clinically and genetically all the distal renal tubular acidosis (dRTA) cases in Cyprus, to study one more family from Greece and to perform the first dRTA pren
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molecular investigation and long term clinical progress in greek cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene
Clinical Genetics, 2006Co-Authors: M Feldman, Avraam Elia, Yiannis Athanasiou, Alkis Pierides, Constantinos Deltas, Marios PrikisAbstract:The spectrum of distal renal tubular acidosis (dRTA) includes a genetically heterogeneous group of inherited conditions of both autosomal-dominant and recessive mode of inheritance. The basic defect is linked to the renal part of acid–base homeostasis, which is partly achieved by the regulated luminal secretion of H+ at the apical surface of the α-intercalated cells of renal collecting ducts. This is coupled to bicarbonate reabsorption with chloride counter transport across the basolateral membranes Here, we describe the molecular findings of the first two Greek Cypriot families with recessive dRTA and the long-term clinical findings in four of five affected members. DNA linkage analysis with four polymorphic markers flanking the ATP6V1B1 gene on chromosome 2 gave evidence for positive linkage; direct DNA analysis by automated DNA sequencing revealed that patients in one family were homozygous for mutation 229+1G>T (IVS7+1G>T) and that patients in the second family were compound heterozygous for 229+1G>T and R157C. The mutations were found on four different haplotypes. Both the mutations were previously reported in patients of Turkish origin. Three known polymorphic variants were also identified. The five patients demonstrated the whole clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis, and episodes of hypokalemic paralysis. Some of the family members are now in their mid 30s and late 20s, and nephrolithiasis with recurrent renal colics is their main problem. Renal function has remained normal. In conclusion, early diagnosis in infancy and prompt treatment with alkali and potassium supplements is of great benefit to the patient with dRTA and ensures normal growth. The identification of responsible mutations facilitates antenatal or postnatal diagnosis in concerned families and improves the prognosis.
Fernando Santos - One of the best experts on this subject based on the ideXlab platform.
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Distal renal tubular acidosis. Clinical manifestations in patients with different underlying gene mutations
Pediatric Nephrology, 2018Co-Authors: Marta Alonso-varela, Helena Gil-peña, Eliecer Coto, Juan Gómez, Julián Rodríguez, Enrique Rodríguez-rubio, Fernando SantosAbstract:Background To evaluate whether there are differences in the phenotype of primary distal renal tubular acidosis (dRTA) patients according to the causal defective gene. Methods Twenty-seven non-oriental patients with genetically confirmed dRTA were grouped according to the identified underlying mutations in either ATP6V1B1 ( n = 10), ATP6V0A4 ( n = 12), or SLC4A1 ( n = 5) gene. Demographic features, growth impairment, biochemical variables and presence of deafness, nephrocalcinosis, and urolithiasis at diagnosis were compared among the three groups. Results Patients with SLC4A1 mutations presented later than those with ATP6V1B1 or ATP6V0A4 defects (120 vs. 7 and 3 months, respectively). Hearing loss at diagnosis was present in the majority of patients with ATP6V1B1 mutations, in two patients with ATP6V0A4 mutations, and in none of cases harboring SLC4A1 mutations. Serum potassium concentration (X ± SD) was higher in SLC4A1 group (3.66 ± 0.44 mEq/L) than in ATP6V0A4 group (2.96 ± 0.63 mEq/L) ( p = 0.046). There were no differences in the other clinical or biochemical variables analyzed in the three groups. Conclusions This study indicates that non-oriental patients with dRTA caused by mutations in the SLC4A1 gene present later and have normokalemia or milder hypokalemia. Hypoacusia at diagnosis is characteristically associated with ATP6V1B1 gene mutations although it may also be present in infants with ATP6V0A4 defects. Other phenotypical manifestations do not allow predicting the involved gene.
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10 expresividad clinica de la mutacion intron 6 1g a en el gen ATP6V1B1 en dos hermanos con acidosis tubular renal distal
Anales De Pediatria, 2007Co-Authors: H Gil, Enrique García, Flor A. Ordóñez, J Rodriguez, E Coto, Fernando SantosAbstract:La acidosis tubular renal distal (ATRD) esta causada por un defecto en la bomba de protones encargada de la secrecion de H+ en el tubulo distal. Aunque pueden existir otros genes implicados, su asociacion con sordera neurosensorial precoz estaria relacionada con mutaciones en el gen ATP6V1B1 . Presentamos dos hermanos diagnosticados de ATRD segun una baja excrecion acida neta e incapacidad para descender el pH urinario en presencia de acidosis metabolica con anion gap normal. Uno de los casos es una nina diagnosticada a los 5 anos de edad por urolitiasis y nefrocalcinosis bilaterales y que presentaba sordera neurosensorial desde los primeros meses de vida. El otro caso es un varon que sufrio fallo de medro y nefrocalcinosis en el primer mes de vida, pero en el que no pudo demostrarse un defecto auditivo neurosensorial durante 5 anos de seguimiento. Mediante secuenciacion del ADN hallamos en ambos casos homocigosis para la mutacion +1G > A en el intron 6 del gen ATP6V1B1 . Estos pacientes ponen de manifiesto la complejidad de la manifestacion clinica en la ATRD con sordera nerviosa: el mismo genotipo puede asociarse a un fenotipo diferente, sin asociarse obligadamente con defectos auditivos congenitos.
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Distal RTA with nerve deafness: clinical spectrum and mutational analysis in five children
Pediatric Nephrology, 2007Co-Authors: Helena Gil, Fernando Santos, Enrique García, María Victoria Álvarez, Flor A. Ordóñez, Serafín Málaga, Eliecer CotoAbstract:Distal renal tubular acidosis (RTA) with nerve deafness is caused by mutations in the ATP6V1B1 gene causing defective function of the H^+-ATPase proton pump. We report five acidotic children (four males) from four unrelated families: blood pH 7.21–7.33, serum bicarbonate 10.8–14.7 mEq/l, minimum urinary pH 6.5–7.1 and fractional excretion of bicarbonate in the presence of normal bicarbonatemia 1.1–5.7%. Growth retardation and nephrocalcinosis, but not hypercalciuria, were common presenting manifestations. Hearing was normally preserved in one of the patients whose sister was severely deaf. One child was homozygous for a known mutation in exon 1: C>T (R31X). Three children were homozygous for a splicing mutation, intron 6 + 1G>A. The other patient was a compound heterozygote, having this mutation and a previously unreported mutation in exon 10: G>A (E330K). Our report shows that hearing loss is not always present in the syndrome of distal renal tubular acidosis with nerve deafness and the absence of hypercalciuria at diagnosis and describes a new mutation responsible for the disease in the ATP6V1B1 gene.